20-45416230-C-T

Position:

• chr20-45416230-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015937.6(PIGT):​c.74C>T​(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIGT NM_015937.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.500

Genes affected

PIGT (HGNC:14938): (phosphatidylinositol glycan anchor biosynthesis class T) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

LOC107985405 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10587603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGT	NM_015937.6	c.74C>T	p.Pro25Leu	missense_variant	1/12	ENST00000279036.12
LOC107985405	XR_001754640.2	n.758G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGT	ENST00000279036.12	c.74C>T	p.Pro25Leu	missense_variant	1/12	1	NM_015937.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444778 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717280

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000473

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1020310). This variant has not been reported in the literature in individuals affected with PIGT-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 25 of the PIGT protein (p.Pro25Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;L;.;.;.;.;.;.;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;N;N;N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.078
Sift	Benign	0.079	T;D;T;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.31	T;T;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.47	P;B;.;.;.;.;.;.;.;.;.;.;.;B;.
Vest4		0.49
MutPred		0.49		Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);Loss of disorder (P = 0.0313);.;
MVP		0.38
MPC		0.18
ClinPred		0.16	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.058
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1227162426; hg19: chr20-44044870;